A New Murine Liver Fibrosis Model Induced by Polyhexamethylene Guanidine-Phosphate

Abstract

Liver fibrosis is part of the wound healing process to help the liver recover from the injuries caused by various liver-damaging insults. However, liver fibrosis often progresses to life-threatening cirrhosis and hepatocellular carcinoma. To overcome the limitations of current in vivo liver fibrosis models for studying the pathophysiology of liver fibrosis and establishing effective treatment strategies, we developed a new mouse model of liver fibrosis using polyhexamethylene guanidine phosphate (PHMG-p), a humidifier sterilizer known to induce lung fibrosis in humans. Male C57/BL6 mice were intraperitoneally injected with PHMG-p (0.03% and 0.1%) twice a week for 5 weeks. Subsequently, liver tissues were examined histologically and RNA-sequencing was performed to evaluate the expression of key genes and pathways affected by PHMG-p. PHMG-p injection resulted in body weight loss of ~15% and worsening of physical condition. Necropsy revealed diffuse fibrotic lesions in the liver with no effect on the lungs. Histology, collagen staining, immunohistochemistry for smooth muscle actin and collagen, and polymerase chain reaction analysis of fibrotic genes revealed that PHMG-p induced liver fibrosis in the peri-central, peri-portal, and capsule regions. RNA-sequencing revealed that PHMG-p affected several pathways associated with human liver fibrosis, especially with upregulation of lumican and IRAK3, and downregulation of GSTp1 and GSTp2, which are closely involved in liver fibrosis pathogenesis. Collectively we demonstrated that the PHMG-p-induced liver fibrosis model can be employed to study human liver fibrosis.

Health Effects Associated With Humidifier Disinfectant Use: A Systematic Review for Exploration

“…Forty-eight published studies using non-human animal subjects or in vitro toxicology studies were included in the review ( Table 3 ). 16 39 40 41 42 43 44 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 To investigate the hazardous effects of humidifier disinfectants, in vitro studies were performed using various cell lines, and toxicity tests were performed using several animal models. Cytotoxicity, lung fibrosis, and pulmonary genotoxicity due to PHMG exposure were described as a consequence of toxicity testing undertaken shortly after HDLI was reported.…”

“… 89 Furthermore, PHMG was found to cause liver fibrosis in male rats in one study. 90 Previously, Leem and Chung 132 estimated that PHMG could have effects not only on the lungs but also on various other organs due to increases in reactive oxygen species and changes in the composition of T lymphocytes. Exposure to PHMG and CMIT/MIT was linked to cardiotoxicity in zebrafish.…”

Tag‐Free Enzymatic Modification for Antibody−Drug Conjugate Production

“…Farnesyl pyrophosphate analogs with azido, aldehyde, and alkynes have also been reported to be transferred by PFTase. PFTase also acts as a prenyltransferase, adding isoprenoid groups to Cys residues in the CaaX recognition tag, where “a” is an aliphatic amino acid and “X” is the amino acid specific to a particular isoprenyltransferase [49] . This technology has been used to produce regioselective and homogeneous ADCs.…”

“…PFTase also acts as a prenyltransferase, adding isoprenoid groups to Cys residues in the CaaX recognition tag, where "a" is an aliphatic amino acid and "X" is the amino acid specific to a particular isoprenyltransferase. [49] This technology has been used to produce regioselective and homogeneous ADCs. ADCs made by combining prenylation conjugation technology with a payload bearing a β-glucuronidase cleavage linker have shown high stability in preclinical evaluations.…”

Antiseptic drugs and disinfectants with experience of the second year of COVID-19 pandemic-related side effects

“…Liver : The causality of PHMG exposure and liver disease remained questionable in the past ( Lachenmeier, 2014 [R]; Lachenmeier et al, 2012 [r]; Solodun et al, 2011 [E]). However, a 5-week study in mice showed that PHMG causes diffuse fibrotic lesions in the liver and that it affects several pathways associated with human liver fibrosis ( Kim et al, 2022 ) [E].…”